Medial Prefrontal Cortex Neural Plasticity, Orexin Receptor 1 Signaling, and Connectivity with the Lateral Hypothalamus Are Necessary in Cue-Potentiated Feeding.

Cognitive processes contribute to the control of feeding behavior and help organism's survival when they support physiological needs. They can become maladaptive, such as when learned food cues drive feeding in the absence of hunger. Associative learning is the basis for cue-driven food seeking and consumption, and behavioral paradigms with Pavlovian cue-food conditioning are well established. Yet, the neural mechanisms underlying circuit plasticity across cue-food learning, cue memory recall, and subsequent food motivation are unknown. Here, we demonstrated the medial prefrontal cortex (mPFC) is a site of learning-induced plasticity and signaling of the neuropeptide orexin within the mPFC mediates cue potentiated feeding (CPF). First, using a marker of neuronal activation, we confirmed that the mPFC is activated during CPF. Next, to assess whether the same mPFC neuronal ensemble is activated during cue-food learning and later CPF, we used the Daun02 chemogenetic inactivation method in transgenic male and female rats. Selective inactivation of the mPFC neurons that were active during the last cue-food training session abolished CPF during test, demonstrating that the mPFC is a site of plasticity. We postulated that integration of food cue memory and feeding motivation requires mPFC communications with lateral hypothalamus and showed that disconnection of that system abolished CPF. Then we showed that lateral hypothalamus orexin-producing neurons project to the mPFC. Finally, we blocked orexin receptor 1 signaling in the mPFC and showed that it is a neuromodulator necessary for the cue-driven consumption. Together, our findings identify a causal function for the mPFC in the cognitive motivation to eat. Obesity has reached epidemic proportions, and the associated health consequences are serious and costly. The causes of obesity are complex because, in addition to physiological energy and nutrient needs, environmental cues can drive feeding through hedonic and cognitive processes. Learned food cues from the environment can powerfully stimulate appetite and food consumption in the absence of hunger. Using an animal model for cue-potentiated feeding, the current study determined the mPFC neuronal plasticity and neuropeptide orexin signaling are critical circuit and neurotransmitter mechanisms involved in this form of cognitive motivation to eat. These findings identify key targets for potential treatment of excessive appetite and overeating.